Research in the Structural Biology & Engineering Laboratory is dedicated to elucidating the molecular basis of the function and (de)regulation of proteins central to cellular signalling networks. The specificity, adaptability and robustness of signalling networks arises from multiple transient interactions among multidomain proteins, often embedded within 'signalosomes'. The intermediate size and dynamic nature of the proteins involved often precludes conventional three-dimensional (3D) structural analysis. Our investigations are therefore based on an integrated structural biology approach that combines functional and structural data from multiple sources (see 'Main Techniques' below). Using these approaches we investigate in particular kinase-mediated signalling networks.
One major focus of the laboratory is on the structure and function of Focal adhesion (FA)–associated proteins. FAs are large macromolecular assemblies through which the actin cytoskeleton is connected to the extracellular matrix (ECM). More than just anchoring the cell, FAs encode the state of the ECM into intracellular biochemical pathways that control cell morphology, migration, differentiation, proliferation, and survival. We have recently determined the molecular basis for site-specific activation of full-length FA kinase (FAK) (Brami-Cherrier, 2014; see Figure). We now use this 3D molecular framework of FAK to understand how the close FAK homologue Pyk2 has evolved the unique capacity of calcium-sensing. Both FAK and Pyk2 have elicited great interest because of their important roles in human health (including cancer invasiveness, heart dysfunction and neurodegeneration). We will therefore also pursue opportunities for medical intervention against erroneous activation of these molecules through targeted intramolecular or intermolecular interaction inhibitors.